The primary objective of this project is to study the conditions for inducing, the characteristics, and the mechanisms of vinblastine (VLB) and vincristine (VCR) neurotoxicity on peripheral and central neurons. This goal is being accomplished through an interdisciplinary study involving functional, biochemical, and morphological approaches. Large single doses of VLB or VCR produce degeneration of peripheral sympathetic nerve terminals. The effects of chronic doses on the development of sympathetic nerve degeneration in the rat are being assessed by measuring endogenous norepinephrine levels in various tissues, the integrity of the integrity of the nerve terminal uptake mechanism, and functional changes such as prejunctional supersensitivity in isolated and intact organ preparations. The effects of VLB and VCR on central neurotransmitters will be determined after intraventricular injections directly into specific brain areas. Central neurotoxicity will be assessed by measuring endogenous transmitter levels and uptake of neurotransmitters into synaptosomal preparations. Fluorescence microscopy and electron microscopy will provide visual confirmation of the loss of norepinephrine and destruction of adrenergic nerve terminals.